TDP-43 as a possible biomarker for frontotemporal lobar degeneration: a systematic review of existing antibodies.

Joery Goossens,Christine Van Broeckhoven,Virginia My Lee,Julie Van Der Zee,Eugeen Vanmechelen,John Q Trojanowski,Sebastiaan Engelborghs

doi:10.1186/s40478-015-0195-1

Abstract

Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer’s disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0195-1) contains supplementary material, which is available to authorized users.

Highlights

Frontotemporal lobar degeneration (FTLD) is the primary cause of early onset dementia after Alzheimer’s disease (AD) [1]
Aggregation of TDP-43 is characteristic for amyotrophic lateral sclerosis (ALS) [16], and clinical and genetic overlap between both disorders has corroborated their association in an FTLD-ALS spectrum [20]
This systematic review provides an overview of antibodies reported to detect TDP-43 pathology

Summary

Introduction

Frontotemporal lobar degeneration (FTLD) is the primary cause of early onset dementia after Alzheimer’s disease (AD) [1]. FTLD is clinically subdivided into behavioral variant frontotemporal dementia (bvFTD) [6] and language variant primary progressive aphasia (PPA) which in its turn comprises three variants [7]. Aggregation of TDP-43 is characteristic for amyotrophic lateral sclerosis (ALS) [16], and clinical and genetic overlap between both disorders has corroborated their association in an FTLD-ALS spectrum [20]. Other neurodegenerative disorders can present with TDP-43 pathology as secondary feature, and this is the case in 20-50% of patients with AD and related tauopathies [14,21]. A comorbid TDP-43 pathology is reported to worsen neurodegeneration independently of AD pathology, leading to a more severe clinical presentation of dementia [22]

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Discussion

Conclusion